Certain substituted benzyl pyridyl-methyl derivatives of 2-,3- or 4-pyridyl carbamates



United States Patent 3,513,171 CERTAIN SUBSTITUTED BENZYL PYRIDYL- METHYL DERIVATIVES OF 2-, 3- 0R 4- PYRIDYL CARBAMATES Kurt Thiele and Walter von Bebenbnrg, Frankfurt, Germany, assignors to Deutsche Goldund Silber- Scheideanstalt vormals Roessler, Frankfurt am Main, Germany N0 Drawing. Continuation-impart of applications Ser. N 0. 637,322, May 10, 1967, and Ser. No. 762,321, Sept. 16, 1968. This application July 25, 1969, Ser. No. 845,058 Claims priority, application Germany, May 12, 1966, D 50,092, D 50,093 Int. Cl. C07d 31/34 US. Cl. 260-295 8 Claims ABSTRACT OF THE DISCLOSURE Pharmacological compounds of the formula:

and their pharmacologically acceptable acid addition salts wherein: R signifies an acylamino group R NH wherein R is an acyl group derived from carbonic acid, carbonic acid semi-morpholide, carbonic acid monoesters, such as the lower alkyl and alkenyl monoesters of carbonic acid, benzoic acids, preferably, substituted benzoic acids, pyridine carboxylic acids, preferably, substituted pyridine carboxylic acids, saturated or unsaturated lower aliphatic mono or dicarboxylic hydrocarbon acids, which, if desired, may be substituted with a morpholino group; each of R R and R can signify the same as R or hydrogen, halogen, lower alkyl, trifluoromethyl, cyano, thiocyanato, mercapto, lower alkylthio, acylthio, hydroxy, lower alkoxy, methylene dioxy, acyloxy, nitro, amino carboxy, carbalkoxy or carbamoyl; R signifies hydrogen or an acyl group; R is hydrogen, lower alkyl or unbranched phenalkyl preferably, phenyl lower alkyl and X signifies :N or :CH, the acyl groups included in R R R or R being as defined for R The benoic acids and the pyridine carboxylic acids from which the acyl groups R are derived can be mono or poly substituted by halogen, hydroxy, trifluoromethyl, lower alkyl, lower alkoxy, methylene dioxy, acyloxy, amino, alkylamino, acylamino, cyano, isocyanato, nitro, mercapto, lower alkylthio, acylthio, carboxy carbethoxy and carbamino. The acyl groups in such substituents again being as defined.

RELATED APPLICATIONS This application is a continuation-in-part of applications Ser. No. 637,322, filed May 10, 1967 and Ser. No. 762,321 filed Sept. 16, 1968.

US. application Ser. No. 481,938, filed Aug. 23, 1965, now Pat. No. 3,375,257 granted on Mar. 26, 1968 concerns related compounds.

3,513,171 Patented May 19, 1970 BACKGROUND AND SUMMARY OF THE INVENTION The present invention concerns compounds of the formula:

and their pharmacologically acceptable acid addition salts wherein R through R and X are as defined above.

These compounds differ from the class of compounds discribed in application Ser. No. 481,938 by the inclusion of the group between and the phenyl or pyridyl nucleus and furthermore by the fact that they possess marked analgesic properties not possessed by the compounds of Ser. No. 481,938 and furthermore also possess antipyretic and antiinflammatory (antiphlogistic) activity. The analgesic action of the compounds according to the invention already occurs at dosages at which the antiinflammatory activity is not yet detectable.

The compounds according to the invention, for instance, exhibit a strong analgesic activity in the mouse tail test according to Haflner, a strong antiinfiammatory activity on albumen edema of the rat paw and a good antipyretic action on yeast fever of the rat at oral dosages between 1 and 300 mg./kg. The compounds exihibit a favorably low toxicity which expressed as LD 50 in mg./kg. of between 400 and 2700 when orally administered to mice.

The following indications come into question for the compounds according to the invention:

Indications as pain relieving medicament:

Pains of all geneses Indications as antiinflammatory medicament:

Chronic polyarthritis Rheumatic diseases Posttraumatic inflammations Swellings resulting from fractures Thrombophlebitis of all forms, including postoperative Bursitis Synovitis Collagenoses (polymyositis, periarteriitis) Gout Intraperitoneal adhesions Indications as antipyretic medicament:

Fevers in illnesses of all geneses The application can be enteral or parenteral, for example, in the form of tablets, capsules, pills, suppositories, solutions, suspensions, injections and the like.

The novel compounds according to the invention can 3 be prepared by conventional methods, such as, for instance:

(a) Reacting a compound of the formula:

with a compound of the formula:

in which Z is either a halogen atom or the group NHR or the group OR in which R is hydrogen, lower alkyl or phenyl, with or without a solvent, preferably, in the presence of a condensing agent at raised temperature.

(b) Condensing a compound of Formula I with a compound of the formula:

wherein Y is a halogen atom, or a hydroxy, lower alkoxy or phenoxy group or the group SO CH or 80 W in which W is hydrogen or alkali metal with a compound of the formula:

HN-CH with or without a solvent as in (a) and, if desired, simultaneously or subsequently acylating any amino group present and/or, if desired, converting any functional groups present by known methods, such as, alkylation, acylation, saponification or by reaction with ammonia or an amine. The bases thus obtained can be converted into their salts. The bases which contain an optically active carbon atom and which as a rule are obtained in racemate form can be resolved in a known manner into their optically active isomers with an optically active acid and fractional precipitation or crystallization. It, however, also is possible to employ optically active starting materials.

It is generally advisable to employ temperatures between about 80 and 250 C. in methods (a) and (c) but in method (a) when Z is a hydroxy group higher temperatures of up to about 400 C. may be necessary. Method (b) expediently is carried out at temperatures between about 20 and 150 C. Water, alcohols, benzene, toluene, dioxane, dimethylformamide, N-methylpyrrolidone, dimethylsulfone, sulfolane, tetramethyl urea, for instance, may be used as solvents.

The condensing agents for methods (a) and when Z and Y represent halogen, for instance, can be sodium acetate, sodium amide, alkali metal carbonates and tertiary amines. Zinc chloride, phosphorus oxychloride, ptoluene sulfonic acid, iodine and the like can be used as condensing agents in method (a) when Z is NHR Zinc chloride, calcium chloride, triethyl phosphate, for instance, can be used in methods (a) and (c) when Z and Y signify a hydroxy group or R 0. Zinc chloride and 4 copper chloride can, for instance, be used as condensing agent in method (c) when Y is W.

The subsequent acylation of amino groups can be carried out by known methods using the corresponding acid chlorides, anhydrides or esters. If the amino group carrying R is not to be acylated, acid chlorides or anhydrides are preferably used at temperatures below 60 C., preferably at 0 to 30 C. When more than one amino group is present in addition to that carrying R partial acylation (not considering the amino group carrying R can be effected by employing only enough acid halide for acylation of one amino group, whereby the non-acylated amino group is converted to the hydrochloride.

The acylation of the amino group carrying R can also be carried out with acid halides but at temperatures above 60 C., for instance, 70 to C. Longer reaction periods are required for such acylation.

In the event any of the substituents R -R in the compounds obtained by methods (a)-(c) is a nitro group, it can be reduced by catalytic hydrogenation, for instance, with Raney nickel, palladium or platinum as catalyst to an amino group. Temperatures between 20 and 80 C. and gauge pressures of 5 to 20 atmospheres can be employed for such hydrogenation. The reduction can also be effected with nascent hydrogen, such as, for example, with zinc/HCl or with salts of hydrogen sulfide in alcohol/Water at about 70 to 120 C. or with activated aluminum in wate rcontaining ether at 20 to 40 C. or with Sn (II) chloride/HC].

The following examples will serve to illustrate the compounds according to the invention with reference to a number of representative specific embodiments. The hydrochlorides of various of the compounds produced in such examples can be converted to the free base by treatment with ammonia or NaOH.

Example 1 (a) 2-benzylamino-5-acetamino pyridine 80 g. of 2-chloro-S-nitro-pyridine were added portionwise while stirring at C. to 110 g. of benzylamine. After completion of the exothermic reaction the reaction mixture was poured into water and the precipitated product filtered off and recrystallized from ethanol. Yield 100 g. (82% of theory) of 2-benzylamino-5-nitro pyridine of a melting point of 133-4 C. After addition of 30 g. of Raney nickel to the latter, it was hydrogenated in 500 ml. of methanol at 50 C. at a gauge pressure of 20 atmospheres. After completion of the hydrogenation the catalyst was filtered olf and 56 g. (67% of theory) of 2-benzylamino-5-amino-pyridine were recovered by distillation from the filtrate after it had been boiled down. Its boiling point at 0.2 torr was -l85 C.

10 g. of acetic acid anhydride were added portionwise to a solution of 20 g. of 2-benzylamino-5-amino pyridine in benzene while maintaining a temperature below 40 C. The solution from which a portion of the product had separated was boiled down and the residue stirred with ether and the solid product filtered off, triturated with a small quantity of aqueous soda and recrystallized from methanol.

Yield 13 g. of 2-benzylamino-S-acetamino-pyridine of a melting point of 14014l C.

(b) Z-benzylamino-S-carbethoxyamino-pyridine HCl NH-CHzQ HCI N 9.6 ml. of chloroformic acid ethyl ester were added portionwise to a mixture of 20 g. of Z-benzylamino-S- amino pyridine, 8.5 ml. of pyridine and 100 ml. of acetone and the mixture stirred for 30 minutes at room temperature. The solution was boiled down and the residue dissolved in benzene, the solution shaken with water and the benzene phase dried and boiled down. The residue was dissolved in methanol and acidified with isopropanolic HCl and clarified over charcoaLThe hydrochloride which crystallized out was filtered off and recrystallized several times from methanol-ether. Yield 11 g., melting point 145-6 C.

Example 2 (a) 2-(2-picolylamino) 5 carbethoxyamino-pyridine-HCl.

A mixture of 108 g. (1 mol) of 2-picolylan1ine, 1.5 liters isopropanol, 158 g. (1 mol) of 2-chloro-5-nitropyridine and 138 g. of powdered potassium carbonate was boiled under reflux while stirring for 7 hours. After cooling, the solids were filtered olf and freed from inorganic salts by repeatedly washing with water. Yield 210 g. (86.7% of theory) of 2-picolylamino-S-nitro-pyridine of a melting point of 156-7 C.

190 g. (0.78 mol) of the latter were hydrogenated in 1.5 liters of methanol after addition of 30 g. of Raney nickel at 60 C. under a gauge pressure of 60 atmospheres. The solution was filtered, boiled down and the residue distilled under vacuum at 0.7 torr at 210220 C. The solid distillate was recrystallized from isopropanol. Yield 152 g. (97% of theory) of 2-(2-picolylamino)-5- amino-pyridine of a melting point of 100 C. The substance was sensitive to air.

10.8 g. of chloroforrnic acid ethyl ester were added portionwise to a solution of 20 g. (0.1 mol) of the 2-(2- picolylamino)-5-amino-pyridine in 100 ml. of acetone and 8 ml. of pyridine. After standing for 6 hours the reaction mixture was poured into 300 ml. of water, alkalized to a pH of 8-9 and extracted with benzene. The benzene solution was dried and boiled down. Isopropanolic HCl was added to the residue and the 2-(2-picolylamino)-5- carbethoxyamino-pyridine-HCl recrystallized twice from 1:1 ethanol-methanol. The yield was 7.2 g. (21.4% of theory). Its melting point was 230 C.

(b) 2- (2-picolylamino 5-propionylamine-pyridine was produced analogously employing propionyl chloride instead of the chloroformic acid ethyl ester. The product was recrystallized as the base from isopropanol. Its melting point was 126-7 C. Yield 37% of theory.

2-(2-picolylamino) (p-chl0robenzamino)- pyridine 17.5 g. of p-chlorobenzoyl chloride were added portionwise while stirring to a mixture of 20 g. (0.1 mol) of 2-(2-picolylamino)-5-amino-pyridine in 100 ml. of acetone and 8 ml. of pyridine at 30 C. After standing for 6 hours the reaction mixture was poured into water and alkalized with NaOH. The reaction product which precipitated was filtered off and recrystallized twice from methanol. Yield 14.9 g. (44% of theory). Melting point 6 Example 3 (a) 2-amino 3 carbethoxyamino 6 benzylaminopyridine-HCI 172 g. (1.6 mol) of benzylamine were gradually added to 69.6 g. (0.4 mol) of 2-amino-3-nitro-6-chloro-pyridine in 500 ml. of n-propanol while stirring at 90 C. An exothermic action occurred. After the addition was completed, the mixture was stirred for 30 minutes at 100 C. and dissolved in 1 liter of acetone. Sufiicient water was added to effect clouding. The 2-amino-3-nitro-6-benzylamino-pyridine which crystallized out was analysis pure. Yield 87 g. (94% of theory). Melting point 132 C.

99 g. of the product produced as described was hydrogenated in 400 ml. of dioxane in the presence of 30 g. of water free Raney nickel and 40 g. of Water free sodium sulfate at 50 C. under a gauge pressure of 20 atmospheres. The hydrogenation mixture was filtered under nitrogen. The base, 2,3-diamino-6-benzyl-amino-pyridine crystallized out after addition of a small quantity of ether and gasoline. The base was very sensitive to oxygen and on access to air discolored to a deep blue. Its melting point was -90 C. The hydrochloride could be obtained directly from the filtered hydrogenated solution by addition of isopropanolie HCl. Yield 65% of theory. Melting point 217-8 C.

40 ml. of chloroformic acid ethyl ester were added to 50 g. of the crude 2,3-diamino-6-benzyl-amino-pyridine (base) in 300 ml. of dioxane and the mixture stirred until the reaction subsided. The 2-amino-3-carbethoxy product crystallized out and was filtered off and recrystallized from ethanol. Yield 62 g. Melting point 208-209 C.

(b) 2-amino 3 car-bopropoxyamino-6-benzylaminopyridine -HCl.

25 ml. of chloroformic acid propyl ester were added to 25 g. of crude 2,3-diamino-6-benzylamino-pyridine produced as above in 200 ml. of dioxane and the mixture stirred until the reaction subsided. The product which crystallized out was filtered off and recrystallized from ethanol. Yield 40 g. Melting point 225-30 C.

(c) 2-amino 3 acryloylamino-6-benzylamino-pyridine-HCl was prepared analogously using 15 ml. of acrylic acid chloride instead of the chloroformic acid propyl ester. Yield 30 g. Melting point 230-5 C.

(d) N-[Z-amino 6 benzylaminopyridyl (3)1-carbamic acid isopropyl ester-HCl Example 4 (a) 2 amino-3-carbethoxyamino-6-(m-trifluoromethyl-benzyl) -pyridine HCl 80 g. (0.46 mol) of 2-amin0-3-nitro-6-chloropyridine were added portionwise to a mixture of 80 g. (0.46 mol) of m-trifluoromethyl-benzylamine, 200 ml. of n-propanol and 36.5 g. of powdered potash at C. while stirring. After the exothermic reaction was completed the mixture was stirred for a further 30 minutes at 90 C. The mixture was poured into water and after standing for some time the supernatant liquid was decanted off from the precipitated product. The precipitate was dissolved in benzene and the solution dried and filtered and gasoline added to the filtrate until clouding occurred. The crystallized yellow product, 2 amino 3 nitro-6-(m-trifluoromethyl-benzylamino)-pyridine, was filtered off. Yield 74 g. Melting point 105-8 C.

34 g. of this product were hydrogenated at 50 C. at a gauge pressure of 50 atmospheres in 450 ml. of dioxane in the presence of water free Raney nickel and water free sodium sulfate. After filtering the resulting hydrogenated solution, the 2,3-diamino-6-(m-trifluoromethyl-benzyl)- pyridine-dihydrochloride was precipitated therefrom with the aid of isopropanolic HCl. After filtering it off it was recrystallized from ethanol. Yield g. Melting point 205 C.

14 ml. of chloroformic acid ethyl ester were added portionwise to a hydrogenated solution produced as above. After minutes the reaction product crystallized out which was filtered off after cooling and recrystallized from isopropanol-ether-gasoline. Yield 20 g. of Z-amino- 3-carbethoxyamino 6 (m-trifluoromethyl-benzyl)-pyridine-HC]. Melting point 213 C.

(b) 2-amino 3 carbphenethoxyamino-6-(m-trifiuoromethyl-benzylamino -pyridine HCl.

12 g. of chloroformic acid-fi-phenethyl ester were added portionwise to a hydrogenated solution as produced in 4(a). After the reaction subsided a small quantity of ether was added gradually while stirring. The product crystallized slowly and after filtering off was recrystallized from methanol/water. Yield 30 g. Melting point 150- 60 C.

(c) 2-amino 3 acryloylamino-6-(m-trifluoromethylbenzylamino)-pyridine hydrochloride was prepared in a manner analogous to that of 4(b) using acrylic acid chloride instead of the chloroformic acid-B-phenethyl ester. Yield 42% of theory. Melting point 230-5 C.

Example 5 (a) d,l-2-amino 3 propionylamino-6-[l-phenyl-ethyl-(1)-amino]-pyridine-HC1 C Ha 17.3 g. (0.1 mol) of 2-amino-3-nitro-6-chloro-pyridine were added portionwise while stirring into 48 g. (0.1 mol) of d,l-l-phenyl-ethylamine at 90 C. After the reaction subsided, the reaction mixture was heated for a further 10 minutes to 100 C. and thereafter 75 ml. of glacial acetic acid and 200 ml. of water were added thereto. The syrup which separated out was taken up in ether and the ether solution washed thoroughly with water and dried. Upon addition of isopropanolic H'Cl the crystalline hydrochloride precipitated. The latter was filtered off and dissolved in 1:1 methanol-water and aqueous ammonia added thereto. The oil which separated out crystallized upon rubbing. Yield 21 g. (81% of theory) of d,l-2- amino 3 nitro-6-[1-phenyl-ethyl-(l)-amino]-pyridine. Melting point 1046 C.

A mixture of 103 g. (0.4 mol) of such 2-amino-3-nitro product produced as described, 600 ml. of dioxane, 50 g. of water free sodium sulfate and g. of Raney nickel was hydrogenated at C. under a gauge pressure of 50 atmospheres to produce the corresponding 2,3-diamino product.

A of the hydrogenated solution thus obtained was reacted with 10 ml. of propionyl chloride. After 10 minutes the reaction product crystallized out. After one hours standing it was filtered off and recrystallized from a small quantity of water. Yield 12 g. (42% of theory) of d,l-2- amino-3-propionylamino-6- l-phenyl-ethyl-(l amino]- pyridine-HCl. Melting point 20510 C.

(b) A further quantity of the hydrogenated solution HCl obtained as above was reacted analogously with chloroformic acid ethyl ester to produce d,l-2-amino-3-carbethoxyamino 6 [1-phenyl-ethyl-(1)-amino]-1-pyridine- I-ICl. It crystallized slowly from dioxane/ether. Yield 8 g. (24% of theory). Melting point 1557 C.

The 2-amino-3-nitro compounds which were the starting bases for the preparation of the acylated compounds in the following examples were produced analogously to the 2-amino-3-nitro compounds employed in Examples 3-5 using Z-amino-3-nitro-6-chloro-pyridine and the appropriately substituted benzyl amine.

Example 6 (a) 2 amino-3-carbethoxyamino-6-p-methoxy-benzylamino-pyridine -HCl A solution of 110 g. of 2-amino-3-nitro-6-p-methoxybenzylamino-pyridine in 1 liter of dioxane containing 50 g. of Raney nickel was hydrogenated at 50 C. under a gauge pressure of 50 atmospheres. The hydrogenated solution was filtered and 40 ml. of chloroformic acid ethyl ester added thereto portionwise while stirring. After 2 hours standing the precipitate was filtered off and recrystallized from methanol. Yield 86 g. Melting point 202 C. (decomposition) (b) Z-amino 3 pivaloylamino-6-p-methoxy-benzylamino-pyridine -HCl.

The procedure under (a) was repeated using pivalic acid chloride instead of the chloroformic acid ethyl ester. Yield 17 g. from 27.5 g. of the nitro compound. Melting point 225-6 C.

Example 7 (a) 2-amino 3 carbethoxy-G-p-chlorobenzylaminopyridine -HCl l NHC o o C1115 CH2NH\\NLNH2 g. of 2-amino-3-nitro-6-p-chlorobenzylamino-pyridine in 500 ml. of dioxane were hydrogenated as in Example 6(a) and a quater of the hydrogenated solution reacted with 10.8 ml. of chloroformic acid ethyl ester and the product recrystallized as in Example 6(a). Yield 6 g. Melting point 2l920 C.

(b) 2-amino-3-acetamino 6 p chlorobenzylaminopyridine-hydrochloride.

A quarter of the hydrogenated solution obtained under (a) was reacted with 7.8 ml. of acetyl chloride and processed analogously. Yield 7.5 g. Melting point 260 C. (decomposition).

-HCl

Example 8 (a) 2 amino 3 carbethoxy-6-(3,4-methylene-dioxybenzylamino)-pyridine -HCl.

102 g. of 2-amino-3-nitro-6-(3,4-methylene-dioxybenzylamino)-pyridine in 500 ml. of dioxane were hydrogenated in a manner analogous to that of Example 7(a) and a quarter of the hydrogenated solution reacted with 9.5 ml. of chloroformic acid ethyl ester and processed as in Example 7(a) except recrystallization was from water. Yield 20.2 g. Melting point 213 C.

(b) 2-amino 3 propionylamino-6-(3,4-methylene-dioxybenzylamino)-pyridine-HC1 was prepared analogously using propionyl chloride. Yield 20.5 g. Melting point 241 C.

Example 10 (a) 2-amino 3 carbethoxyamino-6-p-methylbenzylamino-pyridine -HCl.

76 g. of 2-amino-3-nitro 6 p-methyl-benzylaminpyridine in 440 ml. of dioxane were hydrogenated as in Example 7(a) and one quarter of the hydrogenated solution analogously reacted with 8.2 ml. of chloroformic acid ethyl ester. The recrystallization was from water. Yield 12.1 g. Melting point 2089 C.

(b) 2-amino-3-propionylamino 6 p methylbenzylamino-pyridine-HCI was produced analogously using propionyl chloride. Yield 15.1 g. Melting point 268-9 C.

Example 11 (a) 2 amino 3 carbethoxy-6-(2,4-dimethylbenzylamino) -pyridine HCl.

27 g. of 2-amino-3-nitro-6-(2,4-dimethylbenzylamino)- pyridine in 200 ml. of dioxane were hydrogenated as in Example 7(a) and the hydrogenated solution reacted with ml. of chloroformic acid ethyl ester and processed as in Example 7(a). Yield 15.8 g. Melting point 2l67 C.

(b) 2 amino-3-carbeth0xyamino-6-(2,5-dimethylbenzylamino)-pyridine-HC1 was prepared analogously employing the 2,5-dimethylbenzylamino starting compound instead of the 2,4-dimethylbenzylamino compound. Yield 12.9 g. Melting point 2178 C.

Example 12 (a) 2 amino-3-carbethoxyamino-6-(3,4-dimethylbenzylamino -pyridine-HC1.

37 g. of 2-amin0-3-nitro-6-(3,4-dimethylbenzylamino)- pyridine in 350 ml. of dioxane were hydrogenated as in Example 7(a) and one-half of the hydrogenated solution reacted with 69 m1. of chloroformic acid ethyl ester. Yield 13.1 g. Melting point 221 C.

(b) 2-amino 3 propionylamino-6-(3,4-dimethylbenzylamino)-pyridineHCl was prepared analogously using propionyl chloride. Yield 13.1 g. Melting point 250 C.

(decomposition).

Example 13 2 isopropylamino-3-carbomethoxyamino-6-benzylamino-pyridine HCl.

19 g. of isopropylamino-3-nitro-6-benzylamino-pyridine in 200 ml. of dioxane were hydrogenated as in Example 7(a) and the hydrogenated solution reacted with 5.8 ml. of chloroformic acid methyl ester at 15 C. After 2 hours stirring at room temperature, the product was filtered off and recrystallized from isopropanol/ ether. Yield 15 g. Melting point 202 C. (decomposition).

Example 15 2-amino-3-nitro-6-p-fluorobenzylamino-pyridine 65 g. (0.52 mol) of p-fiuorobenzylamine and 100 g. (0.725 mol) of powdered potassium carbonate in 500 ml. of n-propanol were heated to C. 87 g. (0.5 mol) of 2- amino-3-nitro-6'chloropyridine were added portionwise while stirring within 10 minutes. The mixture was then stirred for 3 hours at boiling temperature. After cooling, the reaction mixture was poured into 1.5 liters of water. The product which precipitated was filtered off and recrystallized from dioxane/ water. Yield 52.4 g. Melting point 172-174 C.

Example 16 2 amino 3 carbethoxyamino-6-p-fiuorobenzylaminopyridine-hydrochloride 26.2 g. (0.1 mol) of 2-amino-3-nitro-6-p-fluorobenzylamino-pyridine were hydrogenated in 250 ml. of dioxane after addition of 15 g. of Raney nickel at 50 C. under a gauge pressure of 30 atmospheres. The solution was filtered off from the catalyst and reacted with 10.8 ml. (0.113 mol) of chloroformic acid ethyl ester while stirring. The reaction product which crystallized after about 15 minutes, was filtered off and recrystallized from water. Yield 19 g. Melting point 214215 C.

Example 17 HCl 2-benzylamino-5-morpholinocarbonylamino-pyridine After addition of 300 ml. of dioxane 64 g. (0.32 mol) of 2-benzylamino-S-aminopyridine and 90 g. (0.6 mol) of morpholinocarboxylic acid chloride were boiled under reflux for 30 minutes. During the boiling process, the hydrochloric salt of 2-benzylamino-5-morpholinocarbonylamino-pyridine crystallized out. After cooling the obtained salt was filtered 01f, washed with isopropanol, and dissolved in 1 liter of water. The base was precipitated with the aid of 7 N ammonia, filtered off, and recrystallized from ethanol. Yield 26 g. Melting point 148-l50 C.

Example 18 2-benzy1amino-5-morpholinoacetamido-pyridine A mixture of 8 g. (0.029 mol) of 2-benzylamino-5- chloroacetamido-pyridine, 12 ml. (0.093 mol) of morpholine, and 40 ml. of isopropanol was boiled under reflux for six hours. After cooling 200 ml. of water were added to the reaction mixture. The product, 2-benzylamino-5-morpholinoacetamido-pyridine, which precipi tated was filtered off, washed with water, and recrystallized from ethanol. Yield 6 g. Melting point 135137 C.

Example 19 d-2-amino-3-carbethoxy 6-(1,2-diphenyl-ethylamino)- pyridinel-mandelic-acid-salt) (d-torm) (l-form) 24 g. of d 2 amino-3-nitro-6-(l,Z-diphenyl-ethylamino)-pyridine were hydrogenated in 450 ml. of dioxane with 15 g. of Raney nickel and 40 g. of magnesium sulfate in an autoclave at 50 C. and a gauge pressure of 40 atmospheres. The hydrogenated solution was freed from the catalyst and drying agent and reacted with g. of chloroformic acid ethyl ester. After 30 minutes 1.5 liters of a 1:1 ether/gasoline mixture was added to the solution and the solution decanted off from the syrupy precipitate which separated out. The precipitate was dissolved in 200 ml. of methanol and neutralized with ammonium hydroxide and the resulting base shaken out with 500 ml. of ether. A solution of l-mandelic acid in isopropanol was added to the ether solution of the base. The mandelic acid salt crystallized upon rubbing and addition of gasoline. Yield 30 g.; melting point 134 C. [a] =+3.5 C.

Example 20 2 amino 3-carbethoxy-6-(l-p-fiuoropheny1-2-phenyl ethyl-amino)-pyridine.

47 g. of 2-amino-3-nitro-(1-p-fluorophenyl-2-phenylethyl-amino)-pyridine were hydrogenated in 450 ml. of dioxane with g. of Raney nickel and 40 g. of magnesium sulfate in an autoclave at 50 C. and a gauge pressure of 40 atmospheres. The hydrogenated solution was freed from the catalyst and drying agent and reacted with 15 ml. of chloroformic acid ethyl ester. After 30 minutes 1.5 liters of a 1:1 ether/ gasoline mixture was added to the solution and the solution decanted off from the syrupy precipitate which separated out. The precipitate was dissolved in 200 ml. of methanol and neutralized with ammonium hydroxide and the resulting base shaken outwith 500 ml. of ether. The .organic phase was washed three times with water and the desired product crystallized out. It was filtered oil? and recrystallized from n-propanoldioxane. Yield 10 g.; melting point 8889 C.

Example 21 (a) 2 amino-3-propionyl-amino-6-(o-methoxy-benzylamino)-pyridine-HCl.

41 g. of 2-amino-3-nitro-6-(o-methoxy-benzyl-amino)- pyridine were hydrogenated in 300 ml. of dioxane with the aid of Raney nickel as in Example 20.1 g. of propionyl chloride were added to the hydrogenated solution after removal of the catalyst and drying agent. After 30 minutes etherzgasoline (1: 1) was added to the solution until clouding occurred. The desired compound crystallized out gradually. After 2 hours the crystals were filtered off and recrystallized from methanol. Yield 29 g.; melting point 210 C.

(b) 2 amino-3-carbethoxy-amino 6 (o-methoxybenzyl-amino)-pyridine-HCl was prepared in an analogous manner using chloroformic acid ethyl ester instead of the propionyl chloride. Yield 24 g.; melting point 153- 155 C.

'(c) 2 amino-3-carbethoxy-amino 6 (m-methoxybenzyl-amino)-pyridine-HCl was prepared in a manner analogous to that under (1)) using 38 g. of the corresponding 6-(m-methoxy-benzyl-amino) substituted pyridine instead of the 6-(o-methoxy-benzyl-amino) substituted pyridine as starting material. The product was recrystallized from ethanol. Yield 40 g.; melting point 180181 C.

(d) 2-amino-3-carbethoxy-amino 6 (3,4-dimethoxybenzyl-amino)-pyridine-HCl was prepared in a manner analogous to that under (b) using 22 g. of the corresponding 3,4-dimethoxy-benzyl-amino derivative of pyridine instead of the o-methoxy-benzyl-amino derivative as starting material. The product was recrystallized from ethanolether. Yield 20 g.; melting point 198199 C.

'(e) 2 amino 3 carbethoxy-amino-6-(2-methyl-4- methoxy-benzyl-amino)-pyridine'HCl was prepared in a manner analogous to that under (b) using 17.5 g. of the corresponding 2-methyl-4-methoxy-benzyl-amino derivative of pyridine instead of the o-methoxy-benzyl amino derivative as starting material. Crystallization of the product was promoted by gradual addition of an equal volume of ether while stirring for several hours. Yield 10 g.; melting point 208209 C.

(f) 2-amino-3-carbethoxy-amino 6 (p-ethoxy-benzylamino)-pyridine'HCl was prepared in a manner analogous to that under (b) using 40 g. of the corresponding pethoxy-benzyl-amino derivative of pyridine instead of the o-methoxy-benzyl-amino derivative as starting material. The product was recrystallized from ethanol. Yield 30 g.; melting point 208-210 C.

(g) 2 amino-3-carbethoxy-amino 6 (3-methoxy-4- hydroxy-benzyl-amino)-pyridine-HC1 was prepared in a manner analogous to that under (b) using 26.5 g. of the corresponding 3-methoxy-4-hydroxy-benzyl-amino derivative of pyridine instead of the o-methoxy-benzyl-amino derivative as the starting material. Yield 22 g.; melting point 176 C.

(h) 2 amino- 3 carbethoxy-amino 6 (3,5-dimethoxy-benzyl-amino)-pyridine-HCl was prepared in a manner analogous to that under (b) using 42 g. of the corresponding 3,S-dimethoxy-benzyl-amino derivative of pyridine instead ofthe o-methoxy-benzyl-amino derivative as the starting material. The product was recrystallized from 70% ethanol. Yield 33 g.; melting point 208 C.

(i) 2-a-mino-3-carbethoxy-amino 6 (2,4-dimethoxybenzyl-amino) -pyridine-HC1.

45 g. of 2-amino 3 nitro-6-(2,4-dimethoxy-benzylamino)-pyridine were hydrogenated in a manner analogous to that under (a) and the resulting hydrogenated solution reacted with 16.5 ml. of chloroformic acid ethyl ester. The reaction solution was mixed with 1 liter of a 1:1 ether-gasoline mixture and the resulting syrupy precipitate dissolved in ml. of H 0 and acidified with 2 ml. of concentrated HCl. The desired compound crystallized out pure. Yield 22 g.; melting point 8990 C.

Example 22 2-(p-methoxy-benzyl-amino) 3 carbeth0xy-amino-6- amino-pyridine-maleic acid salt CIT-C O OH moxoomn i cn-coon Example 23 2-amino 3 carbethoxy-amino-6-(1,2-diphenyl-ethyl amino) -pyridine HCl.

19 g. (0.057 mol) of a-amino-3-nitro-6-(1,2-diphenylethyl-amino)-pyridine in 250 ml. of dioxane with 5 g. of Raney nickel and 15 g. of MgSO were hydrogenated at 60 C. under a gauge pressure of 40 atmospheres. The

hydrogenated solution was filtered and 65 ml. of chloroformic acid ethyl ester (0.068 mol) added to the filtrate. After 2 hours the solution was stirred up with 150 ml. of 2% aqueous ammonia. The syrupy precipitate was taken up in ether and 10 ml. of 9 n-isopropanolic HCl added to the solution. The precipitate which formed was filtered oil and reprecipitated from acetone-ether. Yield 11.2 g.; melting point 159-161 C.

Example 24 2-arnino 3 (p-methoxybenzoyl-amino)-6-(1,2-diphenyl-ethyl-amino -pyridine HCl.

17.3 g. (0.057 mol) of 2,3-diamino-6-(1,2-dipheny1- ethyl-amino)-pyridine (produced as described in Example 23) in 250 ml. of dioxane were stirred with 11 g. (0.065 mol) of p-methoxy-benzoyl chloride. The desired product precipitated out and Was washed with dioxane and water. Yield 24.5 g.; melting point 9596 C.

Example 25 2-amino-3-carbethoxy 6 (1,3-diphenyl-propyl-amino)-pyridine-(maleic acid salt) Example 26 2 amino 3 morpholinocarbonylarnino 6 (p methoxy benzylamino) pyridine hydrochloride 31 grams of 2-amino-3-nitro-6-(p-methoxybenzylamino)-pyridine were catalytically hydrogenated at 50 C. and 50 atmospheres (gauge) with Raney nickel in 200 ml. of dioxane. The hydrogenated solution was filtrated and treated directly With 17.2 ml. of morpholino carboxyl chloride with stirring. After an hour the crystallized compound was removed with suction and washed with alcohol-ether. The product was analytically pure, M.P. 201- 2 C.

Example 27 2 amino 3 morpholinocarbonylamino 6 [1 (2,4 dimethylphenyl) ethyl (1) amino] pyridine hydrochloride on. H3

28 grams of 2-amino-3-nitro-6-[1-(2,4-dimethylphenyl)-ethyl-(1)-amino]-pyridine were hydrogenated as in Example 26 and reacted with 14.6 ml. of morpholinocarbonyl chloride. The product was crystallized by the addition of ether, M.P. 196-200 C.

ll 4- Example 28 2 amino 3 carbethoxyamino 6 (p methylmercaptobenzylamino) pyridine hydrochloride NHC O O CzHs HCl 20 grams of 2-amino-3-nitro-6-(p-methylmercaptobenzylamino)-pyridine in 500 ml. of tetrahydrofurane were reduced with stirring in a nitrogen atmosphere with activated aluminum chips with the addition of 13 ml. of water. The temperature was held at 15 C. After an hour there was added 30 grams of magnesium sulfate, the mixture stirred for a short time, quickly suction filtered and the filtrate reacted with 8 ml. of chloroformic acid ethyl ester with stirring. The reaction product crystallized and was recrystallized from methanol, M.P. 206-210 C.

Example 29 2 amino 3 carbethoxyamino 6 [0c (p methylphenyl) 5 phenylethylamino] pyridine hydrochloride 40 grams of 2-arnino-3-nitro-6-[ot-(p-methylphenyD- B-phenylethylamino]-pyridine were hydrogenated in a manner analogous to that in Example 19 and the filtrated reaction solution reacted wtih 15 ml. of chloroformic acid ethyl ester. After addition of ether-benzine (1:1) the hydrochloride crystallized out, M.P. 142144 C.

- IICl NHz Example 30 2 amino 3 carbethoxyamino 6 (p-carboxy-bem zylamino) pyridine-HCI 29 grams of 2-amino-3-nitro-6'(p-carboxybenzylamino)pyridine were hydrogenated in ml. of dimethyl formamide and 200 ml. dioxane with 10 grams of Raney nickel at 70 C. and 60 atmospheres (gauge). The hydrogenated solution was treated with 10.8 ml. of chloroformic acid ethyl ester. The reaction solution was filtered after 10 minutes and treated with ether. The separating syrup crystallized. It was removed by suction filtration and recrystallized from ethanol-water, yield 15 grams M.P. 241- 243 C.

NHCOOC2H5 HCl NHz Example 31 2 amino 3 carbethoxy 6 (2,4 dichlorobenzylamino) pyridine HCl 31 grams of 2-amino-3-nitro-6-(2,4-dichlorobenzylamino) pyridine were hydrogenated in 500 m1. of dioxane with 5 grams of Raney nickel and 30 grams of MgSO in an autoclave at 50 C. and 40 atmospheres (gauge). The hydrogenated solution was freed of catalyst and drying agent and treated with 11 ml. of chloroformic acid ethyl ester. The compound crystallized out in pure form. It was filtered off with suction, washed with acetone and dried, yield 28 grams, M.P. 196-197 C.

- HCl 15 Example 32 2 amino 3 carbethoxyamino 6 (a p chlorophenyl) p3 phenylethylamino) pyridine l I NHCOOCZI'B c1 HNH iron 70 grams of 2-amino-3-nitro-6-(a-p-chlorophenyl-fiphenylethyl-amino)pyridine were hydrogenated in the manner set forth in Example 19. The solution in dioxane obtained was reacted With 20.5 ml. of chloroformic acid ethyl ester. The reaction solution was then treated with enough ether-benzine (1:1) that the reaction product separated as a syrup. This syrup was dissolved in a little methanol, the base set free with aqueous ammonia, extract by shaking with ether and the ether solution washed whereby the base separated as crystals, M.P. 142144 C.

Example 33 2 amino 3 carbethoxyamino 6 [c (2,4 dimethylphenyl) [3 phenylethylamino] pyridine hydrochloride oH QJm-NH 38 grams of 2-amino-3-nitro-6-[u-(2,4-dimethylphenyl)-fl-phenylethylamino]-pyridine were hydrogenated in the manner set forth in Example 19 and the filtrated reaction solution reacted With ml. of chloroformic acid ethyl ester. After addition of ether-benzine (1:1) the hydrochloride crystallized out, M.P. 164 C.

Example 34 2 amino 3 carbomethoxyamino 6 [a (2,4 dimethylphenyl) ,8 phenylethylamino] pyridine CHalHNH 24 grams of 2-amino-3-nitro-6-[a-(ZA-dimethyIphenyl)-B-phenylethylamino]-pyridine were hydrogenated in the manner set forth in Example 19 and the filtrated solution reacted with 7 ml. of chloroformic acid methyl ester. The reaction solution was then treated with sufficient ether-benzine 1:1) that the reaction product separated as a syrup. This syrup was dissolved in a little methanol, the base set free with aqueous ammonia and extracted by shaking with ether. By subsequent washing of the ether solution with water the base separated as crystals, M.P. 144 C.

NHCOOCHs NHz N/ Example 2 amino 3 carbethoxyamino 6 [a (3 trifluoromethylphenyl) fl phenylethylamino] pyridine N NH2 16 separated as a syrup. This syrup was dissolved in a little methanol, the base set free with aqueous ammonia and extracted by shaking with ether. After washing the ether solution with water the base separated as crystals, M.P. C.

Example 36 2 amino 3 carbethoxyamino 6 p iso propylbenzylaminopyridine hydrochloride I NHCOOCzIIs 60 grams of 2-amino-3-nitr0-6-p-isopropylbenzylaminopyridine hydrochloride were hydrogenated in 500 ml. in the manner set forth in Example 19 and a third of the solution reacted with 7.6 ml. of chloroformic acid ethyl ester. After addition of ether-benzine (1:1) the hydrochloride crystallized out and was recrystallized from ethanol, M.P. 217-218 C.

Example 37 2 amino 3 carbethoxyamino 6 (3 methoxy 4- hydroxybenzylamino) -pyridine hydrochloride NHCOOCzHs HCl 2 carbethoxyamino 3 amino 6 (2,4 dimethylbenzylamino)-pyridine hydrochloride 16 grams of 2 carbethoxyamino 3 carbobenzyloxyamino-6-(2,4-dimethylbenzylamino)-pyridine in 400 ml. dioxane were hydrogenated (debenzylated) with 3 grams 10% palladium on charcoal at room temp. and atmospheric pressure; 800 ml. of hydrogen were absorbed. The solution was filtered, acidified with 6 N isopropanolic HCl and stirred, until the amorphous precipitate was crystalline. It Was recrystallized from Water. M.P. 180 C. (dec.). Yield 10' g.

The term lower alkyl includes alkyl groups of 1 to 6 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, hexyl, butyl, sec. butyl and the like. The halogen usually has a molecular weight of up to 80, i.e. it is fluorine, chlorine, or bromine.

What is claimed is:

1. A compound selected from the group consisting of compounds of the formula:

, NOOOC2H5 Ra X and their pharmaceutically acceptable acid addition salts where R is selected from the group consisting of lower alkyl and phenyl lower alkyl,

R is selected from the group consisting of hydrogen,

amino, and lower alkylamino, R and R when taken jointly are methyleneoxy, R

when taken singly is selected from the group consisting of hydrogen, lower alkyl, halogen, lower alkoxy,

hydroxy, trifluoromethyl, carboxy and lower alkylthio, R when taken singly is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy and halogen,

R is selected from the group consisting of hydrogen,

lower alkyl and unbranched phenyl lower alkyl, and

X is selected from the group consisting of =N and =CH with the proviso that when X is =N R and R are both hydrogen.

2. A compound according to claim 1 where R is in the two position.

3. A compound according to claim 2 where R is hydrogen and X is =CH.

4. A compound according to claim 3 where R is selected from the group consisting of hydrogen, lower alkyl, chloro, fiuoro, methoxy, ethoxy, hydroxy and trifluoromethyl and R is selected from the group consisting of hydrogen, methyl and methoxy.

5. A compound according to claim 4 wherein R is amino.

6. A compound according to claim 5 wherein R is hydrogen.

7. A compound according to claim 1 wherein R when 18 taken singly is selected from the group consisting of hydrogen, lower alkyl, halogen, lower alkoxy, trifiuoromethyl and R when taken singly is selected from the group consisting of hydrogen and lower alkyl, and R is selected from the group consisting of hydrogen and lower alkyl,

8. A compound according to claim 1 wherein R When taken singly is selected from the g oup consisting of hydrogen, lower alkyl, halogen, lower alkoxy, hydroxy and trifluoromethyl and R when taken singly is selected from the group consisting of hydrogen, lower alkyl and lower alkoxy.

References Cited UNITED STATES PATENTS 3,375,257 3/1968 Thiele et al. 260295 HENRY R. JILES, Primary Examiner A. L. ROTMAN, Assistant Examiner U.S. Cl. X.R. 

